Potential treatments in neuropsychiatry (cognitive dysfunction) are the targets of psychostimulants. Cognitive dysfunction is a core feature of complex mental disorders like schizophrenia. Modafinil, a psychostimulant, differs from other arousal-enhancing agents in chemical structure, neurochemical profile, and behavior effects. It has a lower liability for abuse and lower risk for adverse events on the cardiovascular system. Amphetamine, another psychostimulant has pronounced effects on generation of anxiety and fear as shown by increased amygdala reaction for fearful faces tasks. Previous fMRI studies examined the effect of Modafinil only on information processing which supports executive cognition, but also has been shown to have pronounced effects on emotional behavior. In this study we used cognitive, imaging and basic science methods to test our hypothesis and identify a possible treatment approach for cognitive dysfunction. We examined healthy subjects in a double-blind, placebo controlled study using BOLD fMRI. Subjects performed emotional information processing task (face matching) to activate the amygdala, and cognitive tasks: working memory (2-Back) and the Variable Attentional Control to activate the prefrontal region. They also underwent clinical assessments which included: blood pressure, heart rate, Hamilton anxiety scale, POMS (profile of mood state). We hypothesized there would be no change in amygdala reaction or decreased reaction and improved cortical efficiency defined as engaging less cortical activity or more focused cortical activity for a similar level of task performance vs. placebo. Our result on the effects of chronic low dose Modafinil was significantly decreased amygdala activation to anxiety and fearful stimuli on drug vs. placebo, which is in stark contrast to other psychostimulants, like low-dose amphetamine. In addition, we observed an increase in negative coupling between the supragenual cingulate and the amygdala in a functional connectivity analysis. The molecular mechanism of the Modafinil effect on amygdala reactivity is unknown. It is possible that the increase in negative coupling between the supragenual cingulate and amygdala suggest a top-down control mechanism may be responsible at the neural systems level for the dampening effect on amygdala reactivity. Reduced amygdala reactivity may then lead to the reduction in positive coupling with the supragenual cingulate. Additional studies will be needed to determine the functional directionality and to confirm our hypothesis. Alternatively, the reduction in amygdala reactivity on Modafinil could result from alterations in intra-amygdalar signaling due to changes in any one or a combination of norepinephrine, dopamine, serotonin, or gamma-Aminobutyric acid levels. It has been previously reported that reduction of amygdala reactivity is observed after administration of drugs that act on noradrengic system and the serotonin system. Because Modafinil acts on both systems as well as other neurotransmitter pathways, makes it difficult to determine the mechanism through which Modafinil affects amygdala reactivity. Additional studies will be needed to identify the mechanism on which Modafinil acts to modulate amygdala reactivity. Executive cognitive tasks comparing the same level of task performance, Modafinil reduced BOLD signal in prefrontal cortex and anterior cingulate. These results are in agreement with previously published reports which suggest improvement in the efficiency of information processing in brain regions highly populated with catecholaminergic neurons. Although not significant, there was a trend for reduced anxiety, decreased fatigue, increased activity, and decreased anger while taking Modafinil. In our study, improved cortical efficiency meant engaging less cortical activity or having more focused cortical activity on a similar level of task performance vs. placebo. These changes in BOLD signal were observed in the absence of any difference in accuracy, reaction time during 2-Back working memory task, and therefore reflected an improvement in prefrontal cortex efficiency while taking Modafinil. The variable attention control task showed an increase in demand on the level (low-intermediate-high) of attentional control with a significant drug-effect in the anterior cingulate activation in placebo vs. Modafinil. Future studies will implore event-related working memory paradigms to define subprocesses that are modulated by the drug. Using a larger sample size following imaging quality exclusion and examining a within subject dose-response effects will strengthen our analyses. Additional studies will also be needed on the circuit underlying anxiety to other drugs to elucidate the neurotransmitter systems implicated in Modafinil effect on amygdala. This is the first in vivo study in humans of multiple effects of Modafinil. In summary, low doses of Modafinil appears to show no adverse effect on the cardiovascular system, improves the efficiency of cognitive information processing, and reduces amygdala reactivity for anxiety to fearful stimuli. In another study that used genes associated with schizophrenia, we looked at gene-gene interactions to better characterize the impact of a single nucleotide polymorphism (SNP) rs1130233 in AKT1 on human medial temporal lobe (MTL) development and plasticity. This specific AKT1 SNP was previously reported to impact protein expression, prefrontal function and increases risk for schizophrenia, also affects MTL structure and memory function. We found interactions between the AKT1 SNP with BDNF (brain-derived neurotrophic factor) and COMT (catechol-o-methyltransferase) SNPs (Val66Met and Val158Met respectively). BDNF and COMT also impact MTL biology, as related to AKT1. We found epistasis between functional variants in all three genes on schizophrenia risk and pharmacogenetics interactions of AKT1 with effects on cognition and brain volume as measured by AKT1 activators, lithium and sodium valproate. Our findings suggest that AKT1 affects risk and cognitive deficits in part thru genetic interactions related to brain neuroplasticity and development, and these AKT1 effects may be modulated with pharmaceuticals. AKT1 influences memory-dependent hippocampal activity, gray matter volume for patients on mood stabilizers, has epistatic interactions with BDNF and COMT on risk for schizophrenia (as seen in casecontrol sample), and pharmacogenetics effects on cognition and brain structure in schizophrenia. A convergent series of human studies identified effects of an AKT1 allelic variation in memory-dependent neuroplasticity and structural brain processes related to normal brain development as well as to schizophrenia, and epistatic interactions with neurotrophic and dopaminergic processes that modulate these AKT1 effects. AKT1 regulation through pharmacologic was further associated with effects on schizophrenia-related cognition and the corresponding prefrontal-MTL brain structure in schizophrenia patients. AKT1 and related neuroplasticity and developmental pathways may, therefore, genetically influence cognition and risk for schizophrenia through effects that may be pharmacologically manipulated.